This invention relates to methods and compositions for treating viral infections including retroviruses such as HIV and Hepatitis C in mammals.
The disease now known as acquired immunodeficiency syndrome (AIDS) was first recognized as early as 1979. The number of cases reported to the Centers for Disease Control and Prevention (CDC) increased dramatically each year since then, and in 1982 the CDC declared AIDS a new epidemic. It has also been estimated that over 40 million people have been diagnosed with AIDS.
Retroviruses were proposed as the causative agent of AIDS. Recently, human immunodeficiency virus type 1 (HIV) has emerged as a preferred name for the virus responsible for AIDS. Antibodies to HIV are present in over 80% of patients diagnosed as having AIDS or pre-AIDS syndrome, and it has also been found with high frequency in identified risk groups.
AIDS is characterized by a compromised immune system attributed to the systemic depletion of CD4+T lymphocytes (T cells) and the unresponsiveness and incompetence of remaining CD4+T cells. The level of CD4+T cells serves as a diagnostic indicator of disease progression. HIV infected CD4+T cells are known to be directly cytopathic to other CD4+T lymphocytes and this single cell killing event is initiated via HIV envelope protein (gp120/41) interaction with the CD4 molecule. Highly virulent isolates of HIV induce syncytia (defined as  greater than 4 nuclei within a common cell membrane), a process associated with rapid loss of CD4+T cells and disease progression.
HIV-I infection in humans causes general immunosuppression and involves other disorders, such as blindness, myelopathy, or a dementing neurological disorder, i.e., the AIDS dementia complex, the latter of which is a common and important cause of morbidity in patients in advanced stages of infection. HIV-I infection has been documented in various areas of the CNS, including the cerebral cortex, spinal cord, and retina. Price et al. (1988, Science 239:586) and Ho et al. (1989, Annals in Internal Medicine 111:400) review the clinical, epidemiological, and pathological aspects of the AIDS dementia complex, and suggest that the mechanism underlying the neurological dysfunction may be indirect tissue damage by either viral- or cellular-derived toxic substances released by infected cells. The contents of these references is incorporated herein by reference.
There is considerable difficulty in diagnosing the risk of development of AIDS. AIDS is known to eventually develop in almost all of the individuals infected with HIV.
A patient is generally diagnosed as having AIDS when a previously healthy adult with an intact immune system acquires impaired T-cell immunity. The impaired immunity usually appears over a period of 18 months to 3 years. As a result of this impaired immunity, the patient becomes susceptible to opportunistic infections, various types of cancers such as Kaposi""s sarcoma, non-Hodgkins Lymphoma and other disorders associated with reduced functioning of the immune system.
HIV replicates through a DNA intermediate. Each virus particle contains two identical, single-stranded RNA molecules surrounded by the viral nucleocapsid protein. The remaining core of the virus is composed of the capsid and matrix proteins. Enzymes required for replication and integration of the viral genetic materials into the host cells are also contained within the capsid. The outer coat of the virus particle consists of viral envelope glycoproteins and membrane derived from the host cell.
No sufficiently effective treatment capable of preventing the disease is available, although HAART (highly active anti-retroviral therapy) has reversed the immunodeficiency of AIDS. Essentially all patients with opportunistic infections and approximately half of all patients with Kaposi""s sarcoma have died within two years of diagnosis. Attempts at reviving the immune system in patients with AIDS have so far been substantially unsuccessful.
While 3xe2x80x2-azido-3xe2x80x2-deoxythymidine (AZT) has been most often used in treating HIV infection and AIDS, it has considerable negative side effects such as reversible bone marrow toxicity, and the development of viral resistance to AZT by the patient. Thus other methods of treatment are highly desirable.
Viruses traditionally do not respond to antibiotic therapy. Therefore, other treatments are used when treating viral infections. One such recently discovered therapy revolves around the use of protease inhibitors to disrupt the viral replication cycle. Protease inhibitor therapy has the potential to be used in the treatment of a wide range of diseases, including viral infections, such as those caused by retroviruses (e.g., HIV), hepadnaviruses (e.g., hepatitis C virus), herpesviruses (e.g., herpes simplex virus and cytomegalovirus) and myxoviruses (e.g., influenza virus) , as well as parasitic protozoa (e.g., cryptosporidium and malaria) , in cancer chemotherapy and various pathological disorders. However, the protease inhibitors used in HAART have resulted in significant complications including lipodystrophy, hepetic failure and coronary artery disease.
Accordingly, it is desireable to provide improved compositions and methods for the treatment of viral infections, including retroviruses such HIV and hepatitis C.
Generally speaking, the invention involves the administration of a therapeutically effective amount of a pharmaceutical composition, and the composition itself, which is composed of therapeutically effective proportions and quantities of calcium channel blockers (or metabolites thereof) in combination with a quinolines, quinoline-quinones or intermediates or derivatives such as chloroquine. In preferred embodiments, the invention further comprises quercetin or one of its active components. The components combine and interact in a manner to effectively treat retroviruses by reducing viral activity in infected cells.
Accordingly, it is an object of this invention is to provide a safe and effective treatment for viruses such as HIV.